title: Functional analysis of the NH2-terminal hydrophobic region and BRICHOS domain of GKN1.
abstract: Gastrokine 1 (GKN1) protects the gastric antral mucosa and promotes healing by facilitating restitution and proliferation after injury. GKN1 is down-regulated in Helicobacter pylori-infected gastric epithelial cells and loss of GKN1 expression is tightly associated with gastric carcinogenesis. However, the underlying mechanisms as a tumor suppressor are largely unknown. Presently, the hydrophobic region and BRICHOS domain of GKN1, pGKN1(D13N), pGKN1(Δ68-199), and pGKN1(Δ1-67,165-199) were shown to suppress gastric cancer cell growth and recapitulate GKN1 functions. As well, the hydrophobic region and BRICHOS domain of GKN1 had a synergistic anti-cancer effect with 5-FU on tumor cell growth, implying that the NH2-terminal hydrophobic region and BRICHOS domain of GKN1 are sufficient for tumor suppression, thereby suggesting a therapeutic intervention for gastric cancer. Also, its domain inducing endogenous miR-185 directly targeted the epigenetic effectors DNMT1 and EZH2 in gastric cancer cells. Our results suggest that the NH2-terminal hydrophobic region and BRICHOS domain of GKN1 are sufficient for its tumor suppressor activities.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Yoon
authors.forename: Yoo Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Choi
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D044127:Epigenesis, Genetic; D016193:G1 Phase; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D035683:MicroRNAs / Q000096:biosynthesis; D036361:Peptide Hormones / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D016192:Resting Phase, Cell Cycle; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
chemical_list: C477000:GKN1 protein, human; C552431:MIRN185 microRNA, human; D035683:MicroRNAs; D036361:Peptide Hormones; D025521:Tumor Suppressor Proteins
keywords: BRICHOS domain; Cell growth; GKN1; Hydrophobic region; Tumor suppressor activity